title: A c-Myc activation sensor-based high-throughput drug screening identifies an antineoplastic effect of nitazoxanide.
abstract: Deregulation of c-Myc plays a central role in the tumorigenesis of many human cancers. Yet, the development of drugs regulating c-Myc activity has been challenging. To facilitate the identification of c-Myc inhibitors, we developed a molecular imaging sensor-based high-throughput screening (HTS) system. This system uses a cell-based assay to detect c-Myc activation in a HTS format, which is established from a pure clone of a stable breast cancer cell line that constitutively expresses a c-Myc activation sensor. Optimization of the assay performance in the HTS format resulted in uniform and robust signals at the baseline. Using this system, we conducted a quantitative HTS against approximately 5,000 existing bioactive compounds from five different libraries. Thirty-nine potential hits were identified, including currently known c-Myc inhibitors. There are a few among the top potent hits that are not known for anti-c-Myc activity. One of these hits is nitazoxanide, a thiazolide for treating human protozoal infections. Validation of nitazoxanide in different cancer cell lines revealed a high potency for c-Myc inhibition with IC50 ranging between 10 and 500 nmol/L. Oral administration of nitazoxanide in breast cancer xenograft mouse models significantly suppressed tumor growth by inhibition of c-Myc and induction of apoptosis. These findings suggest a potential of nitazoxanide to be repurposed as a new antitumor agent for inhibition of c-Myc-associated neoplasia. Our work also demonstrated the unique advantage of molecular imaging in accelerating discovery of drugs for c-Myc-targeted cancer therapy.
authors.affiliation: Corresponding Author: Sanjiv S. Gambhir, Molecular Imaging Program at Stanford, Stanford University School of Medicine, 318 Campus Drive, East Wing, 1st Floor, Stanford, CA 94305-5427. sgambhir@stanford.edu.
authors.forename: Hua
authors.initials: H
authors.lastname: Fan-Minogue
authors.forename: Sandhya
authors.initials: S
authors.lastname: Bodapati
authors.forename: David
authors.initials: D
authors.lastname: Solow-Cordero
authors.forename: Alice
authors.initials: A
authors.lastname: Fan
authors.forename: Ramasamy
authors.initials: R
authors.lastname: Paulmurugan
authors.forename: Tarik F
authors.initials: TF
authors.lastname: Massoud
authors.forename: Dean W
authors.initials: DW
authors.lastname: Felsher
authors.forename: Sanjiv S
authors.initials: SS
authors.lastname: Gambhir
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000302:isolation & purification / Q000494:pharmacology*; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D004195:Disease Models, Animal; D004354:Drug Screening Assays, Antitumor / Q000379:methods*; D005260:Female; D064593:Heterografts; D057166:High-Throughput Screening Assays / Q000379:methods*; D006801:Humans; D051379:Mice; D008819:Mice, Nude; D057054:Molecular Imaging; D009368:Neoplasm Transplantation; D009574:Nitro Compounds; D016271:Proto-Oncogene Proteins c-myc / Q000037:antagonists & inhibitors* / Q000378:metabolism*; D013844:Thiazoles / Q000302:isolation & purification / Q000494:pharmacology*
chemical_list: D000970:Antineoplastic Agents; C489427:MYC protein, human; D009574:Nitro Compounds; D016271:Proto-Oncogene Proteins c-myc; D013844:Thiazoles; C041747:nitazoxanide